Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase

Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Journal of Virology (Impact Factor: 4.44). 05/2012; 86(15):8259-68. DOI: 10.1128/JVI.00495-12
Source: PubMed


Herpes simplex virus 1 infection triggers multiple changes in the metabolism of host cells, including a dramatic decrease
in the levels of NAD+. In addition to its role as a cofactor in reduction-oxidation reactions, NAD+ is required for certain posttranslational modifications. Members of the poly(ADP-ribose) polymerase (PARP) family of enzymes
are major consumers of NAD+, which they utilize to form poly(ADP-ribose) (PAR) chains on protein substrates in response to DNA damage. PAR chains can
subsequently be removed by the enzyme poly(ADP-ribose) glycohydrolase (PARG). We report here that the HSV-1 infection-induced
drop in NAD+ levels required viral DNA replication, was associated with an increase in protein poly(ADP-ribosyl)ation (PARylation), and
was blocked by pharmacological inhibition of PARP-1/PARP-2 (PARP-1/2). Neither virus yield nor the cellular metabolic reprogramming
observed during HSV-1 infection was altered by the rescue or further depletion of NAD+ levels. Expression of the viral protein ICP0, which possesses E3 ubiquitin ligase activity, was both necessary and sufficient
for the degradation of the 111-kDa PARG isoform. This work demonstrates that HSV-1 infection results in changes to NAD+ metabolism by PARP-1/2 and PARG, and as PAR chain accumulation can induce caspase-independent apoptosis, we speculate that
the decrease in PARG levels enhances the auto-PARylation-mediated inhibition of PARP, thereby avoiding premature death of
the infected cell.

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